Passive antibody administration is the only strategy available for conferring immediate immunity to individuals exposed to biological weapons. Furthermore, toxin-specific antibodies are toxin neutralizing agents par excellence and currently constitute the only means of neutralizing toxins in the human host. The efficacy of antitoxin sera in human therapy is known since the 1890s when Behring and Kitasato developed antisera to tetanus and diphtheria toxins and demonstrated their prophylactic and therapeutic properties. However, despite a century of immunological study we know relatively little about what antibody properties are important for antitoxin efficacy and the mechanisms involved in toxin neutralization are largely conjecture. This application is focused on the generation of antibodies to four toxins: B. anthracis toxins (protective antigen, lethal factor, and edema factor protein subunits) and Staphylococcus aureus enterotoxins with the goal of generating therapeutic antibodies to protect against biological attack with these agents. In addition we will generate neutralizing antibodies to West Nile Virus (WNV). The United States is currently in the midst of an unfolding WNV epidemic and there has been some concern that this agent was deliberately introduced into this country in an act of bioterrorism. While this is unlikely, the morbidity and mortality associated with WNV remain a significant public health concern. Four Specific Aims are proposed: 1) To generate neutralizing (murine and human) monoclonal antibodies to anthrax toxin protein components, S. aureus enterotoxin, and WNV envelope (E) protein; 2) To identify the antibody attributes necessary for optimal toxin and viral neutralizing activity; 3) To generate very high affinity derivatives of neutralizing antitoxin and antiviral mAbs by increasing the rate of somatic hypermutation in selected hybridomas through expression of activation induced deaminase (AID); 4) To identify the mechanism(s) of antibody-mediated toxin and virus neutralization.